Primary B-cell immunodeficiencies are a heterogeneous group of disorders characterized by hypogammaglobulinemia and lack of specific antibody production. The gene defects underlying many of these B-cell immunodeficiencies are unrecognized. However, the most common inherited B- cell defect in male infants has recently been shown to result from mutations in a cytoplasmic protein tyrosing kinase (PTK) called Btk that is required to transduce B-cell antigen receptor binding events to intracellular biochemical pathways. Activation of these signaling pathways by Btk and other PTKs is critical to normal B-cell development and function. We hypothesize that mutations in BCR-associated signaling molecules other than Btk may also be responsible for some forms of inherited B-cell immunodeficiencies. The specific aim of this proposal is to gain insight into the roles of PTKs in B-cell signal transduction and B-cell ontogeny by identifying and characterizing signaling mutations in children with inherited B-cell immunodeficiencies.